Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence

Abstract

It is well established that thyroid dysfunction is linked to an increased risk of cardiovascular morbidity and mortality. The pleiotropic action of thyroid hormones strongly impacts the cardiovascular system and affects both the generation of the normal heart rhythm and arrhythmia. A meta-analysis of published evidence suggests a positive association of FT4 concentration with major adverse cardiovascular end points (MACE), but this association only partially extends to TSH. The risk for cardiovascular death is increased in both subclinical hypothyroidism and subclinical thyrotoxicosis. Several published studies found associations of TSH and FT4 concentrations, respectively, with major cardiovascular endpoints. Both reduced and elevated TSH concentrations predict the cardiovascular risk, and this association extends to TSH gradients within the reference range. Likewise, increased FT4 concentrations, but high-normal FT4 within its reference range as well, herald a poor outcome. These observations translate to a monotonic and sensitive effect of FT4 and a U-shaped relationship between TSH and cardiovascular risk. Up to now, the pathophysiological mechanism of this complex pattern of association is poorly understood. Integrating the available evidence suggests a dual etiology of elevated FT4 concentration, comprising both ensuing primary hypothyroidism and a raised set point of thyroid function, e. g. in the context of psychiatric disease, chronic stress and type 2 allostatic load. Addressing the association between thyroid homeostasis and cardiovascular diseases from a systems perspective could pave the way to new directions of research and a more personalized approach to the treatment of patients with cardiovascular risk.

Keywords: MACE; cardiac electrophysiology; hypothyroidism; sudden cardiac death; thyroid function; thyrotoxicosis; type 2 allostatic load; ventricular arrhythmia.

Figure 1

Types and mechanisms of thyroid hormone signaling. T4 is a prohormone with respect to genomic signaling, but a true fast-acting hormone regarding type 4 action (which is inhibited by the iodothyroacetate TETRAC). Genomic action (type 1, type 2 and mitochondrial signaling) occurs on a slow time scale, whereas non-genomic effects (type 3 and type 4 signaling) represent a fast response (A). Thyroid hormone receptors (THR) usually act as heterodimers. Without thyroid hormone bound they block the transcription together with corepressors. Iodothyronines displace the corepressors and stimulate gene expression together with coactivators (B). Tissue specific distributions of THRs further contribute to the diversity of signaling patterns in the organism (C) (, –69). AF-1, activation function 1; AF-2, activation function 2; D2, type 2 deiodinase; DBD, DNA-binding domain; HAT, histone acetyl-transferase; HDAc, histone deacetylase; LBD, ligand-binding domain; RXR, retinoid X receptor; TRE, thyroid-hormone response element.

Figure 2

Mechanisms of rhythm generation in cardiomyocytes based on a model by Maltsev et al. (85). Two loops, an external membrane loop and an internal calcium loop independently ensure the generation of impulses. Therefore, they provide some redundancy, but they are also intertwined at the stage of slow L-type Ca²⁺ current (I_CaL) activation. Thyroid hormone signaling is able to modulate both loops simultaneously via interfaces at several sites (, , –91), and direct myocardial effects of TSH are largely opposing (92). g_K, ionic conductance for K⁺; INCX, Na⁺/Ca²⁺ exchange current; I_CaT, T-type Ca2+ current; I_f, hyperpolarisation-activated “funny” current; I_K, voltage-gated K⁺ current; I_st, sustained non-selective current; I_to, transient outward potassium current; LCR, local Ca²⁺ release; SERCA, sarcoendoplasmic reticulum Ca²⁺-ATPase; SR, sarcoplasmic reticulum.

Figure 3

Selected mechanisms of arrhythmogenesis by thyroid hormones. T3 (and other active thyroid hormones) upregulate the gene expression of beta1 and beta2 adrenoceptors via classical genomic signaling, but downregulate protective beta3 adrenoceptor expression. The transcription of critical genes for the formation of gap junctions is downregulated as well. Potassium channels are regulated via classical type 1 signaling and via non-genomic effects (type 4 action) as well. Purple arrows indicate the effects of gene expression (transcription, translation and associated processing steps), green arrows visualize the impact of T3-agonistic thyroid hormones.

Figure 4

(A,B) Simplified model of the effects of thyroid hormone signaling facilitating disorders of impulse conduction. Iodothyronine action reduces both the effective refractory period (ERP) and the conduction velocity (θ). As a consequence, the wavelength of excitation λ = ERP x θ may get shorter than the dimensions of a potential re-entry circuit, thus giving rise to re-entrant tachycardia (99).

Figure 5

Flowchart of identified, eligible and included publications.

Figure 6

Hazard ratio for major cardiovascular events (A) and cardiovascular death (B) in relation to TSH concentration (36, 39, 120, 129, 131).

Figure 7

HR for MACE (A) and CVD (B) in relation to FT4 concentration (36, 39, 120, 129, 131).

Figure 8

HR for inclusive MACE (A), study-specific MACE (B), and CVD (C) in subclinical hypothyroidism (, , , , , , , –143).

Figure 9

HR for MACE (A,B) and CVD (C) in subclinical hyperthyroidism (, , , , , –144).

Figure 10

An integrated model for the association between thyroid homeostasis and major cardiovascular events. In the dyshomeostatic type of thyrogenic arrhythmia elevated FT4 concentration, caused by primary thyrotoxicosis, increases the risk for severe arrhythmia as a major cause for cardiovascular mortality. The TSH concentration is reduced in this case, represented by the left, declining, branch of the U-shaped relation between TSH level and risk (A). In the allostatic type, mainly caused by type 2 allostatic load and genetic traits, the set point of thyroid homeostasis is raised, resulting in increased TSH and FT4 concentration and subsequently elevated risk for arrhythmia. This situation is mirrored in the right, rising, branch of the relation between TSH concentration and cardiovascular risk (B). In any case, elevated concentrations of T3, T4 and other T3-agonistic thyroid hormones increase the sensitivity to catecholamines and sympathetic signaling (via upregulated expression of beta1 and beta2 adrenoceptors), thereby contributing to reduced stress tolerance. SPINA-GT, “gain of thyroid,” i.e., thyroid's secretory capacity (150).